Abstract
Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel activity. Small-conductance calcium-activated potassium (SK/KCa) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance.
Original language | English |
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Article number | 113714 |
Number of pages | 13 |
Journal | Biochemical Pharmacology |
Volume | 171 |
Early online date | 15-Nov-2019 |
DOIs | |
Publication status | Published - Jan-2020 |
Keywords
- OXIDATIVE STRESS
- ION CHANNELS
- MITOCHONDRIAL RESPIRATION
- K+ CHANNELS
- CANCER
- THIOREDOXIN
- APOPTOSIS
- INHIBITION
- INDUCTION
- TUMOR